For Frontotemporal Dementia Research Articles

Plasma extracellular vesicle: a novel biomarker for neurodegenerative disease diagnosis

Extracellular vesicles (EVs) are membrane-bound structures that carry proteins, lipids, RNA, and DNA, playing key roles in cell communication and material transport. Recent research highlights their potential as disease biomarkers due to their stability in bodily fluids. This study explores using tau and TDP-43 proteins in plasma EVs as diagnostic biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Analyzing plasma EVs from clinical cohorts, the study found that the 3R/4R tau ratio and TDP-43 levels effectively differentiate between diagnostic groups with high accuracy. Notably, plasma EV biomarkers demonstrate higher diagnostic accuracy and stability compared to direct plasma testing, providing new insights and approaches for future research and clinical practice. Further research is needed to validate these biomarkers in diverse populations and to establish standardized protocols. Future studies should continue to explore the potential of EV biomarkers in a broader range of neurodegenerative diseases and delve deeper into the mechanisms of EV secretion and sorting to enhance their diagnostic utility.

The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study

ObjectiveSensitive cognitive markers are still needed for frontotemporal dementia (FTD). The Benson Complex Figure Test (BCFT) is an interesting candidate test, as it assesses visuospatial, visual memory, and executive abilities, allowing the detection of multiple mechanisms of cognitive impairment. To investigate differences in BCFT Copy, Recall and Recognition in presymptomatic and symptomatic FTD mutation carriers, and to explore its cognitive and neuroimaging correlates. MethodWe included cross-sectional data from 332 presymptomatic and 136 symptomatic mutation carriers (GRN, MAPT or C9orf72 mutations), and 290 controls in the GENFI consortium. We examined gene-specific differences between mutation carriers (stratified by CDR® NACC-FTLD score) and controls using Quade's / Pearson Χ2 tests. We investigated associations with neuropsychological test scores and grey matter volume using partial correlations and multiple regression models respectively. ResultsNo significant differences were found between groups at CDR® NACC-FTLD 0–0.5. Symptomatic GRN and C9orf72 mutation carriers had lower Copy scores at CDR® NACC-FTLD ≥2. All three groups had lower Recall scores at CDR® NACC-FTLD ≥2, with MAPT mutation carriers starting at CDR® NACC-FTLD ≥1. All three groups had lower Recognition scores at CDR® NACC FTLD ≥2. Performance correlated with tests for visuoconstruction, memory, and executive function. Copy scores correlated with frontal-subcortical grey matter atrophy, while Recall scores correlated with temporal lobe atrophy. ConclusionsIn the symptomatic stage, the BCFT identifies differential mechanisms of cognitive impairment depending on the genetic mutation, corroborated by gene-specific cognitive and neuroimaging correlates. Our findings suggest that impaired performance on the BCFT occurs relatively late in the genetic FTD disease process. Therefore its potential as cognitive biomarker for upcoming clinical trials in presymptomatic to early-stage FTD is most likely limited.

Characterization of a diverse Frontotemporal Dementia cohort, enriched for Caribbean Hispanic patients.

AbstractBackgroundThe vast majority of biomedical data currently available for any disease is derived from studies in non‐Hispanic white (NHW) populations. Specifically, clinical information, genetic factors as well as biomarkers for frontotemporal dementia (FTD) have been studied predominantly in those NHW populations. To increase representation in biomedical research, we set out to enroll and characterize a diverse FTD patient cohort enriched for Caribbean Hispanic patients.MethodOur current cohort consists of 89 FTD patients (30% NHW, 67% Hispanic), with continuing enrollment from the University of Miami Hospital Neurology Department in Miami, FL and the Caribbean Center for the Study of Memory and Cognition in San Juan, PR. All patients were evaluated using NACC approved Uniform DataSet (UDS) or equivalent in their preferred language. For ∼65% of the cohort we also completed the NACC FTD module forms. We generated genotyping data (Illumina GDA+Neurobooster array) as well as whole genome sequencing and plasma biomarker data (Quanterix Simoa Neuroplex‐3; Ab40, Ab42, and total tau) for a subset of the cohort.ResultInitial genetic analyses showed none of the Hispanic patients are carriers of known FTD mutations originally identified in NHW patients, including the C9orf72 repeat expansion and reported pathogenic variants in MAPT or GRN. We did not identify a significant difference in age‐at‐onset or Clinical Dementia Rating scores at time of enrollment between NHW and Hispanic patients. Additionally, biomarker data on Aβ40/Aβ42 ratio and total tau levels in a subset of 22 FTD patients (∼12/10 Hispanic/NHW) did not show significantly different levels between patients of both ethnicities.ConclusionGenetic analyses of FTD in underrepresented population groups is necessary as genetic information from research in NHW is not always generalizable across race/ethnicity. We are currently working to expand our efforts to include identification of novel genetic risk factors for FTD in the Hispanic patients using whole genome sequencing, full evaluation of the Neuroplex as well as p‐tau181 and NfL biomarkers in the complete cohort and comparison of clinical presentations between ethnicities. The biomedical characterization of FTD across race/ethnicity will help the understanding of disease mechanisms in all patients ultimately preventing further health disparities.

Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

ObjectiveTo investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD).MethodsEight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M).Results24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone).ConclusionsMotor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

CYLD variants identified in Alzheimer's disease and frontotemporal dementia patients.

Objectives CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population.MethodsIn our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls.ResultsIn the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6–9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2–5, AD and No. 11, FTD). These variants were absent in our in‐house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively.InterpretationOur finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.

Modifiable potential risk factors in familial and sporadic frontotemporal dementia.

ObjectiveOnly a few studies have evaluated modifiable risk factors for frontotemporal dementia (FTD). Here, we evaluated several modifiable factors and their association with disease phenotype, genotype, and prognosis in a large study population including Finnish and Italian patients with FTD and control groups.MethodsIn this case–control study, we compared the presence of several cardiovascular and other lifestyle‐related diseases and education between Finnish and Italian patients with familial (n = 376) and sporadic (n = 654) FTD, between different phenotypes of FTD, and between a subgroup of Finnish FTD patients (n = 221) and matched Finnish patients with Alzheimer's disease (AD) (n = 214) and cognitively healthy controls (HC) (n = 100).ResultsPatients with sporadic FTD were less educated (p = 0.042, B = ‐0.560, 95% CI −1.101 to −0.019) and had more heart diseases (p < 0.001, OR = 2.265, 95% CI 1.502–3.417) compared to patients with familial FTD. Finnish FTD patients were less educated (p = 0.032, B = 0.755, 95% CI 0.064–1.466) compared with AD patients. The Finnish FTD group showed lower prevalence of hypertension than the HC group (p = 0.003, OR = 2.162, 95% CI 1.304–3.583) and lower prevalence of hypercholesterolemia than in the HC group (p < 0.001, OR = 2.648, 95%CI 1.548–4.531) or in the AD group (p < 0.001, OR = 1.995, 95% CI 1.333–2.986). Within the FTD group, clinical phenotypes also differed regarding education and lifestyle‐related factors.InterpretationOur study suggests distinct profiles of several modifiable factors in the FTD group depending on the phenotype and familial inheritance history and that especially sporadic FTD may be associated with modifiable risk factors.

Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia

Interactors of protein products of known genes for frontotemporal dementia (FTD) are likely to be involved in the molecular pathways towards disease. We therefore applied protein interaction network (PIN) analysis to prioritize candidate genes for rare variant association analysis. We created an FTD-PIN starting from known FTD genes downloading their physical interactors and performed functional enrichment analyses. We identified overrepresented processes in FTD and selected genes (n = 440) belonging to these processes for rare variant analysis in a Belgian cohort of 228 FTD patients and 345 controls. SKAT-O analysis suggested TNFAIP3 as the top gene (p = 0.7 × 10−3) reaching near test-wide significance (p = 2.5 × 10−4). We then analyzed the TNFAIP3-subnetwork within the FTD-PIN which indicated enrichment of several immune signaling networks, suggesting that disrupted immune signaling may be implicated in TNFAIP3-related FTD. Our study demonstrates that integration of PINs with genetic data is a useful approach to increase the power for rare variant association analysis. Furthermore, we present a computational pipeline for identifying potential novel therapeutic targets and risk-modifying variants.

Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

BackgroundAstrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and their clinical utility in predicting disease progression.MethodspGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile.ResultsUnlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005).ConclusionspGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

Metabolism in frontotemporal dementia

AbstractBackgroundMetabolic changes incorporating changes in weight, insulin resistance and cholesterol levels have been identified across a number of neurodegenerative conditions. It remains unknown whether these changes represent the result of the process of neurodegeneration affecting critical brain regions involved in metabolic regulation, or are causative, driving the process. Changes in eating behaviour affecting metabolism have been incorporated into the diagnostic criteria for frontotemporal dementia (FTD), and have been shown to potentially effect disease progression, with the potential to aid in clinical phenotyping and early diagnoses.MethodsA number of studies will be reviewed examining changes in eating behaviour in FTD using ecological valid assessments including a test meal approach. The effect that these eating changes have on metabolism will be examined, including changes in cholesterol, and insulin levels and metabolic rate. The role of key brain regions including the hypothalamus will be explored through a number of studies incorporating brain imaging, neuropeptide examination and pathological analyses.ResultsPatients with FTD exhibit a strong fat and sucrose preference, that is not present in normal or Alzheimer’s disease controls. These changes result in increased cholesterol levels and a state of insulin resistance which has been associated with changes in disease progression. Patients with FTD have been found to be hypermetabolic, with increased cholesterol levels, from changes in eating behaviour, likely resulting in improved energy stores in a hypermetabolic state and potentially slowing disease progression. Changes in eating behaviour and metabolism have been linked to changes in key neural networks involving fronto‐insular‐ striatal networks, with connections to the hypothalamus. Changes in key hypothalamic peptides including agouti‐related peptide and leptin have also been implicated in mediating metabolic changes and changes in disease progression.ConclusionsGiven the spectrum of metabolic and eating changes observed in FTD, with emerging evidence that these changes may effect disease progression and prognoses, an understanding of metabolism in FTD may provide a model to better understand the pathophysiology of metabolic change and its complex interaction with the process of neurodegeneration.

Plasma TDP‐43 in neurodegenerative diseases assayed with immunomagnetic reduction

AbstractBackgroundTDP‐43 is a promising biomarker for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, studies on TDP‐43 in human biofluid are rare. In this work, the authors utilized an ultrasensitive technology, called immunomagnetic reduction (IMR), to develop the reagent for assaying TDP‐43.MethodThe preclinical performance characteristics of the TDP‐43 reagent, such as the standard curve, detection limits, assay linearity, dilution recovery range, assay reproducibility, spike recovery, reagent stability, and interference tests, were explored according to the CLSI guidelines. Plasma samples from normal controls (NC, n = 27) and from patients with frontotemporal dementia (FTD, n = 9), Alzheimer’s disease (AD, n = 34) and Parkinson’s disease (PD, n = 10) were collected for TDP‐43 assays using the IMR TDP‐43 reagent.ResultThe low‐detection limit of assaying TDP‐43 was 0.68 fg/ml, and the upper‐detection limit was 100 pg/ml. There was no significant interference effect when assaying TDP‐43 mixed with hemoglobin, bilirubin, intralipid, albumin, etc. The FTD patients had significantly higher levels of plasma TDP‐43 (0.419±0.193 fg/ml) compared to the NC subjects (0.163±0.097 fg/ml), AD patients (0.165±0.082 fg/ml) and PD patients (0.069±0.068 fg/ml). Through analysis of the ROC curve, the cut‐off value of plasma TDP‐43 for discriminating FTD from the other patient groups was 0.237 fg/ml, which resulted a clinical sensitivity of 0.889 and a specificity of 0.831.ConclusionThese results demonstrate the feasibility of assaying plasma TDP‐43 to specifically identify FTD.

Mutation analysis of MFSD8 in an amyotrophic lateral sclerosis cohort from mainland China.

Recent studies have suggested that rare variants in MFSD8 contribute to risk for frontotemporal dementia (FTD). Considering the common underlying pathogenesis and the shared genetic risk between amyotrophic lateral sclerosis (ALS) and FTD, we screened the coding region of MFSD8 in 551 unrelated patients with ALS (510 unrelated sporadic ALS and 41 familial ALS probands) from mainland China by whole-exome sequencing to assess its mutation frequency in patients with ALS and evaluate its association. Two rare deleterious variants, c.343G>A (p. V115M) and c.695T>C (p.L232P), were identified in this study. The variant c.695T>C (p.L232P) has not been previously reported and the carrier of this variant exhibits a relatively younger age of disease onset. Our studies provide some independent evidence showing that the rare variant p.L232P in MFSD8 might be a candidate risk factor for ALS. However, the relatively small sample sizeand the lack of patient-derived cells limit the power of the genetic exploration of this study, further robust multicenter studies with larger sizes and biological experiments with patient-derived cells are needed to elucidate the pathogenesis of the rare variant in MFSD8 in ALS.

AL001 restores CSF PGRN levels and normalizes disease‐associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene

AbstractBackgroundAL001 is a recombinant humanized anti‐Sortilin monoclonal antibody in development for frontotemporal dementia (FTD). Mutations in a single copy of the progranulin gene (GRN) leads to a 50% or greater decrease in the level of circulating progranulin (PGRN) protein levels and are causative of FTD. The disease is associated with increased inflammation and impaired lysosomal function in the brain. The INFRONT Phase 1/1b clinical study AL001‐1 investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL001 in healthy volunteers (HV) and participants with a GRN mutation causative of FTD (FTD‐GRN). In addition, the study investigated the effect of AL001 on disease‐associated biomarkers.MethodA total of 64 participants were enrolled in the AL001‐1 study. In the single dose ascending part of the study, 50 healthy volunteer participants were enrolled with 38 exposed to AL001 and 12 exposed to placebo. The study enrolled 6 asymptomatic FTD‐GRN and 8 symptomatic FTD‐GRN participants. The 8 symptomatic FTD‐GRN participants received 3 doses of 30 mg/kg of AL001 over 4 weeks.ResultTreatment of symptomatic FTD‐GRN participants with AL001 over 4 weeks restored PGRN levels in the cerebrospinal fluid (CSF) to normal levels for more than 8 weeks. To further investigate the effects of restoring PGRN levels, partial normalization of a FTD disease proteomic signature was observed in the CSF 4 weeks after the last dose in multidose treatment group. Compared to healthy volunteers, AL001 treatment rescued cathepsin B (CTSB), a marker of lysosomal function, by 58%. AL001 treatment also partially normalized markers of inflammation and gliosis, osteopontin (SPP1) and chitotriosidase (CHIT1) by 52% and 22%, respectively. In addition to the reversal of these disease phenotypes, a 14% reduction (n.s.) in plasma neurofilament light chain (NfL), a marker of neuron injury and stress, was observed after 8 weeks after the last dose.ConclusionAL001 treatment resulted in a sustained increase in plasma and CSF PGRN in FTD‐GRN mutation carriers. New data showed reduction of NfL and normalization of proteins associated with the disease after one month of dosing. These results have supported progressing AL001 to Phase 2 and pivotal Phase 3 studies.

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis.

The current review provides an up to date overview of the nature and progression of the cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS). Understanding these symptoms has implications for the management of the disease and the design of clinical trials, in addition to the support of patient and caregiver regarding mental capacity and end of life decision-making. Cognitive and behavioural change in ALS are best characterized as the consequence of extensive network dysfunction. 35-45% of ALS patients present with mild-moderate cognitive impairment and comorbid dementia occurs in approximately 14% of patients, the majority of these meeting diagnostic criteria for frontotemporal dementia (FTD). Cognitive change in ALS manifests most commonly as executive dysfunction and language impairment. Behavioural change in the form of apathy, disinhibition, loss of sympathy and empathy, stereotyped behaviours and dietary changes occur. Cognitive and behavioural impairment is an important feature of ALS, and reflects broad network dysfunction of frontostriatal and frontotemporal systems. Cognition and behaviour should be assessed early in the diagnostic process, and data driven approaches should be developed to enable reliable quantitative outcome assessment suitable for clinical trials.

Smoking and Obesity as Risk Factors in Frontotemporal Dementia and Alzheimer’s Disease: The HUNT Study

Background: Few studies have assessed smoking and obesity together as risk factors for frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Objective: To study smoking and obesity as risk factors for FTD and AD. Methods: Ninety patients with FTD and 654 patients with AD were compared with 116 cognitively healthy elderly individuals in a longitudinal design with 15–31 years between measurements of risk factors before the dementia diagnosis. Results: There were no associations between smoking and FTD (p = 0.218; odds ratio [OR]: 0.990; 95% confidence interval [CI]: 0.975–1.006). There were significant associations between obesity and FTD (p = 0.049; OR: 2.629; 95% CI: 1.003–6.894). There were significant associations between both smoking (p = 0.014; OR: 0.987; 95% CI: 0.977–0.997) and obesity (p = 0.015; OR: 2.679; 95% CI: 1.211–5.928) and AD. Conclusion: Our findings suggest that obesity is a shared risk factor for FTD and AD, while smoking plays various roles as a risk factor for FTD and AD.

Research in brief: Symptoms of neuropsychiatric disorders in people living with ALS and their family members

Changes in behaviour are common in Motor Neurone Disease (MND) with up to 15 per cent meeting criteria for frontotemporal dementia (FTD). Higher rates of neuropsychiatric disorders have been found in both MND patients and their family members suggesting a possible overlap between MND, FTD and neuropsychiatric disorders. In this preliminary analysis, we found generally low rates of neuropsychiatric disorders in MND patients and their family members, consistent with healthy controls (HC) and their family members. Future research aims to examine associations between neuropsychiatric symptoms and cognitive and behavioural changes.

Anxiety and Depression as Risk Factors in Frontotemporal Dementia and Alzheimer’s Disease: The HUNT Study

Background: The roles of both anxiety and depression as risk factors for frontotemporal dementia (FTD) and Alzheimer’s disease (AD) have not been previously investigated together. Objective: To study anxiety and depression as independent risk factors for FTD and AD. Methods: Eighty-four patients with FTD and 556 patients with AD were compared with 117 cognitively healthy (CH), elderly individuals. Both cases and controls were participants in the second Health Study of Nord-Trøndelag (HUNT2) from 1995 to 1997, in which depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS). Results: Significant associations were found between anxiety and FTD and between depression and AD. A significantly increased risk of developing FTD was observed in patients who had reported anxiety on the HADS (p = 0.017) (odds ratio [OR]: 2.947, 95% confidence interval [CI]: 1.209–7.158) and a significantly increased risk of developing AD was observed in patients who had reported depression on the HADS (p = 0.016) (OR: 4.389, 95% CI: 1.311–14.690). Conclusion: Our study findings suggest that anxiety and depression may play different roles as risk factors for FTD and AD.

Association analysis of polymorphisms in VMAT2 and TMEM106B genes for Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy

BackgroundThe vesicular monoamine transporter type 2 (VMAT2) and transmembrane Protein 106B (TMEM106B) were reported to be associated with neurodegenerative diseases. Recent studies found that two polymorphisms (rs363371 and rs363324) in VMAT2 might be a risk factor for Parkinson's disease (PD) in Caucasians, while the two other variants (rs1990622 and rs3173615) in TMEM106B increased the risk for frontotemporal dementia (FTD). Considering the overlap between clinical manifestation and pathologic characteristics in neurodegenerative diseases, we conducted a large-sample study to investigate the associations between these four polymorphisms and the risk for PD, sporadic amyotrophic lateral sclerosis (SALS), and multiple system atrophy (MSA) in a Chinese patient population. MethodsA total of 1121 PD, 863 SALS, and 356 MSA patients, as well as 829 healthy controls (HCs), were included in the study. These four polymorphisms were genotyped using Sequenom iPLEX Assay technology. ResultsSignificant differences were found in the genotype distribution of VMAT2 rs363371 between SALS patients and HCs (p=0.001). In an additive model, “GG” of rs363371 significantly decreased the risk for SALS (p<0.001, OR: 0.49, 95% CI [0.36–0.67]). The frequencies of minor alleles for rs1990622 and rs3173615 in TMEM106B were significantly different between PD patients with initial symptoms of tremor and rigidity/bradykinesia (p=0.001), and between patients with initial symptom of rigidity/bradykinesia and HCs (p<0.001). The minor alleles “T” of rs1990622 and “C” of rs3173615 increased the risk for PD patients with initial symptom of rigidity/bradykinesia (OR: 1.21[1.10–1.34] and OR: 1.19[1.07–1.31], respectively). No differences were found in the genotype distribution and allele frequency of the four polymorphisms between MSA patients and HCs. ConclusionIn this Chinese patient population, “GG” of rs363371 in VMAT2 may reduce the risk for SALS, while minor alleles of rs1990622 and rs3173615 in TMEM106B may be associated with PD patients with initial symptom of rigidity/bradykinesia.

Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

No common founder for C9orf72 expansion mutation in Sweden.

Hexanucleotide expansion mutations in the chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). SNP haplotype analyses have suggested that all C9orf72 expansion mutations originate from a common founder. However, not all C9orf72 expansion mutation carriers have the same haplotype. To investigate if the C9orf72 expansion mutation carriers in Sweden share a common founder, we have genotyped SNPs flanking the C9orf72 expansion mutation in cases with FTD, FTD-ALS or ALS to perform haplotype analysis. We have genotyped 57 SNPs in 232 cases of which 45 carried the C9orf72 expansion mutation. Two risk haplotypes consisting of 31 SNPs, spanning 131 kbp, were found to be significantly associated with the mutation. In summary, haplotype analysis on Swedish C9orf72 expansion mutation carriers indicates that the C9orf72 expansion mutation arose on at least two risk haplotypes.